Pharmaceutical compositions for prolonged peptide release and preparation method

ABSTRACT

Solid or semisolid pharmaceutical composition comprising a gellable and water-soluble peptide salt optionally combined with an appropriate excipient, said pharmaceutical composition being characterized in that the peptide salt has a high specific surface area and in that, once injected into a patient, it forms a gel in contact with this patient&#39;s body substances, said gel being capable of releasing the peptide over a prolonged period of at least 15 days.

This application is a 371 of PCT/FR99/00667 filed Mar. 22, 1999.

The invention relates to new pharmaceutical compositions intended forthe sustained release of peptides and to the process for theirpreparation. U.S. Pat. No. 5,595,760 has already described solid andsemisolid pharmaceutical compositions intended for the sustained releaseof peptides, which are composed of a gellable and water-soluble peptidesalt optionally combined with an appropriate monomeric excipient. Afteradministration to a patient, these compositions gel and allow asustained release over a period of at least three days.

These compositions brought a considerable advantage compared with theprior art in terms of the simplicity of their manufacture and use.

The Applicant has now discovered, unexpectedly, that improvedcompositions can be obtained which, while utilizing the same principle,make it possible to obtain a slower release than the conventionalcompositions, it being possible for said release to extend over one,two, three months or more in some cases. In particular, the initial peak(or burst) is reduced.

Furthermore, the compositions of the invention are easier to prepare. Inparticular, the peptide grinding time and the force required for mixingcan be greatly reduced. Also, the characteristics of the compositions ofthe invention are more homogeneous.

Apart from the advantages mentioned above, for the same amount ofpeptide, some of these compositions have the advantage of requiring asmaller injection force, so they are more convenient to use. Thistherefore makes it possible to use syringes with a smaller needlediameter than that which would be necessary for the equivalentcompositions of the prior art.

It is found moreover that these compositions give very good results inthe in vivo tests and that the individual experimental deviations arereduced, making it possible to treat a greater proportion of patientseffectively.

All these advantages are obtained by giving the peptide a higherspecific surface area than that of the non-matrix (gellable)compositions known a person skilled in the art and described in the U.S.Pat. No. 5,595,760. The gellable compositions according to the inventionpreferably use peptides whose specific surface area has been increasedto at least 4 m²/g, and more preferably to 8 m²/g or more, thischaracteristic giving them a slower and more regular release profile.The compositions according to the invention are obtained by using aspecial lyophilization process comprising a flash-freezing phase of apeptide solution, said process being described below.

The invention therefore relates first and foremost to a solid orsemisolid pharmaceutical composition comprising a gellable and solublepeptide salt optionally combined with an appropriate excipient, saidpharmaceutical composition being characterized in that the peptide salthas a high specific surface area and in that, once injected into apatient, it forms a gel in contact with this patient's body substances,said gel being capable of releasing the peptide over a prolonged periodof at least 15 days.

High specific surface area is understood as meaning a specific surfacearea greater than that which would be obtained by a lyophilizationinvolving the slow freezing of a solution of a peptide salt. Slowfreezing is understood as meaning a freezing which is not a flashfreezing as describe hereafter or in the PCT Patent Application WO98/47489.

Preferably, the peptide salt has a specific surface area of at least 8m²/g and, once injected into a patient, it forms a gel in contact withthis patient's body substances, said gel being capable of releasing thepeptide over a prolonged period of at least 15 days.

The invention therefore preferably relates to a solid or semisolidpharmaceutical composition comprising a gellable and soluble peptidesalt optionally combined with an appropriate excipient, saidpharmaceutical composition being characterized in that the peptide salthas a specific surface area of at least 4 or 5 m²/g, preferably 8 m²/g,and in that, once injected into a patient, it forms a gel in contactwith this patient's body substances, said gel being capable of releasingthe peptide over a prolonged period of at least 15 days.

Peptide is understood as meaning either a peptide or a protein. Thepeptide salts which can be used for the invention may be selected inparticular from a group comprising the salts of the followingsubstances: triptorelin, lanreotide, octreotide (as described forexample in Patent EP 29,579), a compound with LH−RH activity, such astriptorelin, goserelin, leuprorelin or buserelin, an LH—RH antagonist, aGPIIb/IIIa antagonist, a compound with a similar activity to aGPIIb/IIIa antagonist, erythropoietin (EPO) or one of its analogues, thevarious types of interferon-α, interferon-β or -γ, somatostatin, asomatostatin derivative such as that described in the European Patent EP215,171, a somatostatin analogue such as that described in the U.S. Pat.No. 5,552,520 (this patent itself includes a list of other patentsdescribing somatostatin analogues, which are incorporated in the presentapplication by way of reference), insulin, a growth hormone (GH), agrowth hormone releasing factor (GHRF), a growth hormone releasingpeptide (GHRP), an epidermal growth factor (EGF), a melanocytestimulating hormone (MSH), a thyrotropin releasing hormone (TRH) or oneof its derivatives, a thyroid stimulating hormone (TSH), a luteinizinghormone (LH), a follicle stimulating hormone (FSH), a parathyroidhormone (PTH) or one of its derivatives, a lysozyme hydrochloride, aparathyroid hormone related peptide (PTHrp), an N-terminal peptidefragment (position 1→34) of human PTH, vasopressin or one of itsderivatives, oxytocin, calcitonin, a calcitonin derivative with asimilar activity to that of calcitonin, a calcitonin gene relatedpeptide (CGRP), glucagon, a peptide similar to glucagon (GLP), gastrin,a gastrin releasing peptide (GRP), secretin, pancreozymin,cholecystokinin, angiotensin, human placental lactogen, human chorionicgonadotropin (HCG), enkephalin, an enkephalin derivative, colonystimulating factor (CSF), endorphin, kyotorphin, interleukins, forexample interleukin-2, tuftsin, thymopoietin, thymostimulin, thymichumoral factor (THF), thymic serum factor (TSF), a derivative of thymicserum factor (TSF), thymosin, thymic factor X, tumour necrosis factor(TNF), motilin, bombesin or one of its derivatives, such as thosedescribed in the U.S. Pat. No. 5,552,520 (this patent itself includes alist of other patents describing bombesin derivatives, which areincorporated in the present application by way of reference), prolactin,neurotensin, dynorphin, caerulein, substance P, urokinase, asparaginase,bradykinin, kallikrein, nerve growth factor, a blood clotting factor,polymixin B, colistin, gramicidin, bacitracin, a protein synthesisstimulating peptide, an endothelin antagonist or one of its derivatives,a vasoactive intestinal polypeptide (VIP), adrenocorticotropic hormone(ACTH) or one of its fragments, a platelet derived growth factor (PDGF),a bone morphogenetic protein (BMP), a pituitary adenylate cyclaseactivating polypeptide (PACAP), neuropeptide Y (NPY), peptide YY (PYY)and a gastric inhibitory polypeptide (GIP). Any water-soluble peptide orprotein salt may also be used by a person skilled in the art if theyconsider it appropriate.

The peptide salt used for the invention will preferably be selected froma group comprising salts of somatostatin or its analogues, particularlylanreotide acetate or octreotide acetate, triptorelin salts,particularly triptorelin acetate, salts of calcitonin or its analogues,salts of LH—RH hormone analogues, salts of GH, GHRF, PTH or PTHrppeptide, and analogues of the latter.

The peptide salts which can be used for the invention are preferablypharmaceutically acceptable salts of organic acids, such as those ofacetic, lactic, malic, ascorbic, succinic, benzoic, methanesulphonic ortoluenesulphonic acids, or pharmaceutically cceptable salts of inorganicacids, such as those of hydrochloric, hydrobromic, hydriodic, sulphuricor phosphoric acids. In particular, they can be acetates of saidpeptide. However, the solubility of the peptide salt must be fairly highin order to allow the freezing of the peptide salt with a small amountof solvent.

Preferably, the specific surface area of the peptide salt will be atleast 4 or 5 m²/g. More preferably, the peptide salt will have aspecific surface area of at least 10 or 15 m²/g. Particularlypreferably, the peptide salt will have a specific surface area of atleast 20 m²/g or even 30 m²/g. These specific surface areas can beobtained using the processes described below or in PCT PatentApplication WO 98/47489.

Said solid or semisolid composition may comprise from 0 to 30% of anexcipient. Excipients which can be used for the invention arepharmaceutically acceptable excipients which facilitate the preparationof the compositions of the invention and/or their administration. Thechosen excipients will have to be water-soluble and biodegradable incontact with the body substances. Notable possibilities are polyalcoholssuch as mannitol and sorbitol, sugars such as glucose and lactose,surfactants, organic solvents or polysaccharides. However, theseexcipients will not be matrix polymers such as polymers of the PLGAtype.

The process which will be used to prepare the pharmaceuticalcompositions of the invention is characterized in that it involves alyophilization step comprising the rapid immersion of a dilute solutionof the peptide salt in a medium whose temperature is below −50° C.

Rapid immersion must be understood as meaning contact with a lowtemperature medium, causing instantaneous freezing of the solution ofwater-soluble substance.

Dilute solution of the peptide salt is understood as meaning a solutionwhose concentration of said peptide salt is less than half thesaturation concentration and preferably less than a quarter of saidsaturation concentration when the latter is at least 200 g/l. Thepeptide salt which can be obtained by this process has a high specificsurface area.

For the lyophilization, the solution may be frozen for example in a trayfloating in a tank of liquid nitrogen, before the actual lyophilizationis carried out.

Preferably, the rapid immersion will be carried out by pouring a dilutesolution of the peptide salt onto a metal plate at very low temperature.The temperature of the plate will preferably be below −70° C. and morepreferably below −80° C. or even −120° C. The peptide salt which can beobtained by this immersion has a very high specific surface area, asdescribed above.

More preferably, in order to obtain the maximum specific surface area,the rapid immersion of the solution will be preceded by a micronizationof the solution of active substance.

If a specific surface area greater than 10 m²/g is required, the processwhich includes a micronization step will preferably be employed. Thespecific surface area obtained for the active substance afterlyophilization will preferably be greater than 15 m²/g. This specificsurface area will even more preferably be greater than 20 m²/g or even30 m²/g. The high specific surface areas will be particularly usefulbecause the force required for injection will be lower and it will bepossible for the needle used for the injection to have a smallerdiameter.

For example, to obtain a very high specific surface area, it may bechosen to atomize the solution by spraying it through an atomizer onto aplate at very low temperature. The temperature of the plate will bebelow −50° C., preferably below −70° C. and more preferably below −80°C. or even −120° C. This temperature may be reached for example byimmersing the metal plate in a very low temperature medium, for exampleliquid nitrogen. In one preferred variant of the invention, the metalplate is hollow and the solution is sprayed inside said plate by meansof an atomizer.

Other freezing techniques can be considered for obtaining a very highspecific surface area, for example atomization of the solution of activesubstance into a precooled bath of a non-solvent for the peptide salt.The non-solvent will preferably be a liquefied gas, for example liquidnitrogen.

Another possibility is to freeze the solution of peptide salt on acooled rotating tray (drum freezing). As indicated previously, thisfreezing will preferably be preceded by a micronization of the solutionof peptide salt.

The specific surface area of the active substance is a favourable factorfor obtaining release over a prolonged period. In fact, particles of apeptide salt which have the same size but different specific surfaceareas will give totally different results.

To vary the specific surface areas obtained, the freezing conditions ofthe solution of active substance may be varied by modifying differentparameters, such as, for example the freezing rate or the concentrationof the solution.

The lyophilization will be carried out under conventional conditionsknown to a person skilled in the art. When the lyophilization iscomplete, the peptide salt is incorporated, optionally with anexcipient, into a solid or semisolid pharmaceutical composition asdescribed above. This solid or semisolid composition can be mixed withwater as described in the U.S. Pat. No. 5,595,760, taking particularaccount of the fact that the water can be present in an amount which isless than 50% of the amount needed to dissolve the peptide saltcompletely, it also being necessary to adapt said amount so as to givesaid composition a semisolid consistency.

Preferably, where possible, the amount of water added will be less than30% and more preferably less than 10% of the amount needed to dissolvethe peptide salt completely.

The proportion of peptide in the compositions according to the inventionwill be determined by the release time which it is desired to achieve,but it cannot exceed a maximum value corresponding to the limitingconcentration at which the solid or semisolid composition can beinjected with a syringe fitted with a needle of customary diameter. Thespecific surface area of the peptide may be varied in order to increasesaid limiting concentration, if necessary; the higher the specificsurface area of the peptide, the lower will be the injection force,making it possible to reduce the diameter of the needle required forinjection.

For example, for lanreotide acetate with a high specific surface area(for example of at least 4 m²/g) obtained by a lyophilization processinvolving a flash-freezing step, it will be possible to use semisolidcompositions with concentrations of 25 or 30% by weight of lanreotideacetate in water (i.e. 20.5 or 24.6% by weight of pure lanreotide). Suchcompositions may easily be injected with needles having an internaldiameter of the order of 1 mm and a length of the order of 32 mm.

Preferably, the compositions of the invention based on lanreotideacetate will comprise from 20 to 35% and more preferably from 25 to 30%by weight of lanreotide acetate.

The mixing of the solid composition and water to give semisolidcompositions is preferably carried out in a device consisting of twointerconnected syringes. For example, the peptide salt is introducedinto one of the syringes, which is then evacuated, the water isintroduced into the other syringe and the mixture is homogenized by thereciprocating movement of the two pistons. In this connection, a personskilled in the art may also usefully consult PCT Patent Application WO97/46202.

As indicated above, the semisolid compositions according to theinvention are preferably used in the pharmaceutical field. Thecompositions according to the invention may be injected into a patient,for example, by using. the devices described in U.S. Pat. No. 5,595,760.

Once injected into a patient, the semisolid compositions according tothe invention form a gel in contact with this patient's body substances,said gel being capable of releasing the peptide over a prolonged periodof at least 15 days. The release period will preferably be at least 1month and more preferably 2 or even 3 months.

Unless defined otherwise, all the technical and scientific terms usedhere have the same meanings as those commonly understood by an ordinaryspecialist in the field to which this invention belongs. Likewise, allthe publications, patent applications, patents and other referencesmentioned here are incorporated by way of reference.

The following examples are given in order to illustrate the aboveprocedures and must not under any circumstances be considered aslimiting the scope of the invention.

EXAMPLES Methods

Measurement of the specific surface area

For all the following examples, the specific surface area of the peptidesalt was determined by the so-called B.E.T method (absorption of anitrogen monolayer on the active substance), a method well known to aperson skilled in the art.

Mixing of the peptide and the water

For all the following examples, the peptide salt and the water are mixedin a device consisting of two interconnected 50 ml syringes. The peptidesalt is introduced into one of the syringes, which is then evacuated,the water is introduced into the other syringe and the mixture ishomogenized by the reciprocating movement of the two pistons.

Example 1

Lanreotide acetate with a specific surface area of 0.61 m²/g isdissolved in water to a concentration of 30 g/l and is frozen by pouringthe aqueous solution obtained into a hollow metal tray cooled on theoutside by liquid nitrogen. This freezes the peptide salt.Lyophilization is then carried out and lanreotide acetate with aspecific surface area of 5.41 m²/g is recovered. 3 g of lanreotideacetate obtained in this way are mixed with 6.927 ml of water to give asemisolid paste. The mixture is then mixed as indicated above to give10.927 g of a compact, homogeneous, semisolid composition. Thiscomposition can be used directly for injection into the subject to betreated.

Example 2

9.0 g of lanreotide acetate with a specific surface area of 1.73 m²/gare dissolved in 300 ml of water. This solution is then sprayed with anatomizer into a hollow metal tray, the bottom of which is immersed inliquid nitrogen. This freezes the peptide salt. Lyophilization is thencarried out and 8.7 g of lanreotide acetate with a specific surface areaof 28.2 m²/g are recovered. 3 g of lanreotide acetate obtained in thisway are mixed with 7.183 ml of water to give a semisolid paste. Themixture is then mixed as indicated above to give 10.183 g of a compact,homogeneous, semisolid composition. This composition can be useddirectly for injection into the subject to be treated.

Examples 3 and 4

The same protocol is used for these two examples:

5 g of lanreotide acetate are dissolved in sterile water to give asolution of the chosen concentration. This solution is atomized with a500 ml sprayer whose jet is adjusted so as to give the finest possibledroplets. The droplets obtained are sprayed into a tray, the bottom ofwhich is immersed in liquid nitrogen. Two temperature probes areintroduced into the tray beforehand so that the change in thetemperature of the product can be monitored.

Once the product is frozen, the tray is introduced into a lyophilizerwhose plate is at about −54° C.

The temperature of the products and that of the plate are left toequilibrate for 1 hour. This leads on to the sublimation phase (thetemperature of the plate is then set at 20° C. and the pressure in thetank at 100 μbar). This phase lasts for about 30 hours. The mean finaltemperature of the product is about 13° C. The secondary desiccationwhich follows (pressure reduced to 50 μbar in the tank) lasts for about24 hours. The mean final temperature of the product is 20° C.

The characteristics of the reagents used and the products obtained aresummarized in the tables below

Characteristics Example 3 Example 4 Weight of lanreotide acetate used(g) 5.00 5.00 Concentration of the solution (g/l) 30 10 Weight oflanreotide acetate recovered (g) 4.54 4.10 Specific surface areaobtained (m²/g) 36 43

Like the lanreotide acetate of Examples 1 and 2, the lanreotide acetateof Examples 3 and 4 can be incorporated into semisolid pharmaceuticalcompositions simply by being mixed with an appropriate amount of water.

Study of the properties of compositions according to the invention

Three tests were performed. The first concerns the force required toinject a dose of the composition obtained according to Example 2, thesecond concerns the in vitro release profile of the same composition andthe third concerns the release profile of the compositions of Examples 1and 2 in dogs, compared with that obtained for a composition which isanalogous but contains a peptide of low specific surface area.

Reference

A composition prepared according to the following protocol was chosen toserve as a reference for the injection force measurement and the invitro test: Lanreotide acetate is dissolved in water to give a solutionwith a concentration of 30 g4, which is poured into a hollow trayimmersed in liquid nitrogen beforehand. The frozen lanreotide acetate isthen lyophilized and incorporated into a solid composition as describedin Example 2 above, 6.817 ml of water being added to 3 g of lanreotideacetate to give 9.817 g of semisolid composition.

Measurement of the force required for injection

A dynamometer is used to measure the force to be applied to the pistonof the syringe in order to move it forward, relative to the displacementof the piston (amount of semisolid composition injected: about 280 mg;as in Example 2, the reference contains about 0.25 mg of lanreotideacetate per mg of semisolid composition). By expressing the displacementof the piston in mm as a function of the applied force in N, athree-phase profile is obtained from which 8 noteworthy values are takenand used to calculate a mean value for the force required for injection.The value recorded for each test is the mean of 5 measurements made onthe same composition.

In vitro release profile

In order to obtain meaningful results, each composition tested isdivided into 6 samples and the mean of the 6 samples is recorded. Ineach case, the semisolid composition to be tested is placed in acylindrical dialysis tube equipped with a semipermeable syntheticmembrane. Both ends of the tube are closed. This tube is placed in 20 mlof 0.9% aqueous NaCI solution, the temperature being set at 37° C. Themedium is stirred (magnetic stirrer). Half an hour, 1 hour, 2 hours 3hours, 4 hours, 24 hours, 48 hours and 72 hours after the start of thetest, samples of the NaCl solution are taken and the lanreotide contentis determined by UV analysis (wavelength: 280 nm). At the end of thetest (after 96 hours for the reference), the residual amount of peptidecontained in the dialysis tube is determined so that the results can beexpressed as the proportion of peptide released relative to the totalinitial amount.

Results

The results obtained are summarized in Table I below:

TABLE I Parameters measured Reference Example 2 Amount of lanreotide in1 mg of gel (in 0.252 0.250 mg) Specific surface area of the lanreotide3.64 28.6 acetate incorporated (m²/g) Force required for injection (N)41.0 27.3 Proportion dissolved after 0.5 h 1.5 1.0 Proportion dissolvedafter 1 h 2.7 2.1 Proportion dissolved after 2 h 5.1 4.0 Proportiondissolved after 3 h 7.2 6.1 Proportion dissolved after 4 h 9.5 8.0Proportion dissolved after 24 h 39.3 29.9 Proportion dissolved after 48h 62.6 38.8 Proportion dissolved after 72 h 77.5 44.7 Proportiondissolved after 96 h 88.4 50.3

Additional measurements were made for Example 2 and show dissolvedproportions of 57.7% after 144 hours, 66.8% after 216 hours and 77.7%after 334 hours.

It is therefore seen that the composition of Example 2, which differsfrom the reference composition by having almost 10 times the specificsurface area, releases the peptide considerably more slowly than thereference composition. Furthermore, the composition of Example 2requires a smaller injection force than the reference composition.

In vivo release profile in does

The reference composition for this test contains 30% by weight oflanreotide acetate with a specific surface area of 0.8 m²/g (obtained bya lyophilization process involving slow freezing), the remainder of thecomposition consisting of water. The concentration of pure lanreotide inthe reference composition and the composition of Example 2 is therefore246 mg per gram of composition.

The tests are performed on two groups of 6 beagle dogs, each dogreceiving an intramuscular injection of 60 mg of reference compositionor composition of Example 2.

Results

The plasma concentrations measured for Examples 1 and 2 (expressed inng/ml) are respectively reported in Table II below:

TABLE II Time Ref. Mean Ex. 2 0 0.000 0.000 0.000 0.083 h 4.909 4.3653.642 0.25 h 20.930 11.348 14.591 0.5 h 32.215 22.711 17.637 1 h 43.21526.863 24.847 2 h 45.208 32.831 29.262 4 h 44.129 30.112 29.696 8 h58.362 30.218 26.713 12 h 48.041 20.831 18.235 1 day 29.462 20.77116.977 2 days 13.677 7.731 13.105 3 days 9.974 8.000 12.248 4 days 6.6836.716 6.520 8 days 3.583 2.564 3.179 11 days 3.225 2.305 2.513 15 days1.786 2.280 2.075 18 days 1.305 2.553 1.481 22 days 1.329 2.317 1.097 25days 1.182 1.582 1.605 29 days 1.024 0.983 0.951 32 days 0.685 0.6969.924 36 days 0.362 0.486 0.714 39 days 0.194 0.521 0.792 43 days 0.2170.443 0.715 46 days 0.189 0.332 0.768 50 days 0.153 0.337 0.511 53 days0.148 0.297 0.513 57 days 0.150 0.228 0.466 60 days 0.131 0.254 0.411 65days 0.094 0.191 0.281 72 days 0.093 0.120 0.312 79 days 0.044 0.1470.157 86 days 0.063 0.068 0.200 93 days 0.050 0.072 0.167 100 days 0.0460.052 0.137 107 days 0.000 0.064 0.107 114 days 0.000 0.057 0.062 122days 0.000 0.034 0.067 128 days 0.000 0.030 0.048 135 days 0.000 — 0.000

These in vivo tests confirm that the initial peak (or burst) isconsiderably reduced for the compositions of Examples 1 and 2 comparedwith an analogous composition containing a peptide of lower specificsurface area. Furthermore, the release becomes too low after 60 days forthe reference composition, whereas for the compositions of Examples 1and 2 it is sufficient to ensure a plasma level in excess of 0.1 ng/mlfor at least 79 days and 107 days respectively.

What is claimed is:
 1. A solid or semi-solid pharmaceutical compositioncomprising a gellable and water-soluble peptide salt and optionally anappropriate excipient, the peptide salt having a high specific surfacearea of at least about 4 m²/g and when injected into a patient, forminga gel in contact with the body substances whereby the peptide isreleased over a period of at least 15 days.
 2. The composition of claim1 wherein the peptide is released over a period of at least one month.3. The composition of claim 1 wherein the peptide is released over aperiod of at least 3 months.
 4. The composition of claim 1 wherein thepeptide salt has a specific surface area of at least 8 m²/g.
 5. Thecomposition of claim 1 wherein the peptide salt has a specific surfacearea of at least 20 m²g.
 6. The composition of claim 1 wherein thepeptide salt has a specific surface area of at least 30 m²/g.
 7. Thecomposition of claim 1 wherein an excipient is present up to 30% byweight of the composition.
 8. The composition of claim 1 wherein theexcipient is at least one member selected from the group consisting ofpolyalcohols, sugars, surfactants, organic solvents and polysaccharides.9. The composition of claim 1 also containing water in an amount lessthan 50% of the amount needed to completely dissolve the peptide saltand adapted to give the composition a semi-solid consistency. 10.Pharmaceutical composition according to claim 1, characterized in thatthe peptide salt is selected from the salts of the following substances:triptorelin, lanreotide, octreotide, a compound with LH—RH activity,such as triptorelin, goserelin, leuprorelin or buserelin, an LH—RHantagonist, a GPIIb/IIIa antagonist, a compound with a similar activityto a GPIIb/IIIa antagonist, erythropoietin (EPO) or one of itsanalogues, the various types of interferon-α, interferon-β or γ,somatostatin, a somatostatin derivative, a somatostatin analogue,insulin, a growth hormone (GH), a growth hormone releasing factor(GHRF), a growth hormone releasing peptide (GHRP), an epidermal growthfactor (EGF), a melanocyte stimulating hormone (MSH), a thyrotropinreleasing hormone (TRH) or one of its derivatives, a thyroid stimulatinghormone (TSH), a luteinizing hormone (LH), a follicle stimulatinghormone (FSH), a parathyroid hormone (PTH) or one of its derivatives, alysozyme hydrochloride, a parathyroid hormone related peptide (PTHrp),an N-terminal peptide fragment (position 1 →34) of human PTH,vasopressin or one of its derivatives, oxytocin, calcitonin, acalcitonin derivative with a similar activity to that of calcitonin, acalcitonin gene related peptide (CGRP), glucagon, a peptide similar toglucagon (GLP), gastrin, a gastrin releasing peptide (GRP), secretin,pancreozymin, cholecystokinin, angiotensin, human placental lactogen,human chorionic gonadotropin (HCG), enkephalin, an enkephalinderivative, colony stimulating factor (CSF), endorphin, kyotorphin,interleukins, for example interleukin-2, tuftsin, thymopoietin,thymostimulin, thymic humoral factor (THF), thymic serum factor (TSF), aderivative of thymic serum factor (TSF), thymosin, thymic factor X,tumour necrosis factor (TNF), motilin, bombesin or one of itsderivatives, prolactin, neurotensin, dynorphin, caerulein, substance P,urokinase, asparaginase, bradykinin, kallikrein, nerve growth factor, ablood clotting factor, polymixin B, colistin, gramicidin, bacitracin, aprotein synthesis stimulating peptide, an endothelin antagonist or oneof its derivatives, a vasoactive intestinal polypeptide (VIP),adrenocorticotropic hormone (ACTH) or one of its fragments, a plateletderived growth factor (PDGF), a bone morphogenetic protein (BMP), apituitary adenylate cyclase activating polypeptide (PACAP), neuropeptideY (NPY), peptide YY (PYY) and a gastric inhibitory polypeptide (GIP).11. Pharmaceutical composition according to claim 10, characterized inthat the peptide is selected from the group consisting of salts ofsomatostatin or its analogues, triptorelin salts, salts of calcitonin orits analogues, salts of LH—RH hormone analogues, salts of GH, GHRF, PTHhormones or PTHrp peptide, and analogues of the latter. 12.Pharmaceutical composition according to claim 10, characterized in thatthe peptide is triptorelin acetate.
 13. Pharmaceutical compositionaccording to claim 11, characterized in that the peptide is triptorelinacetate.
 14. Pharmaceutical composition according to claim 11,characterized in that the peptide is lanreotide acetate.